Efficacy and safety of disitamab vedotin (RC48) in combination with sintilimab and XELOX for perioperative therapy of G/GEJ cancer with HER2 overexpression: Preliminary results of a prospective, single-arm, phase II study.

Abstract

382 Background: Locally advanced HER2-positive gastric/gastroesophageal junction (G/GEJ) adenocarcinoma (cT3-4a/bN+) has a poor prognosis with neoadjuvant chemotherapy. The HER2-targeting antibody-drug conjugate disitamab vedotin (DV, RC48) shows efficacy in advanced disease, but its combination with sintilimab (anti-PD-1) and XELOX in the perioperative setting remains unexplored. This phase II trial (NCT06227325) conducted in China evaluates the efficacy and safety of this regimen for resectable HER2-positive (IHC 3+/2+) G/GEJ adenocarcinoma. Methods: Patients with resectable HER2+ (IHC 3+/2+) G/GEJ cancer (cT3-4aN1-3M0, AJCC 8th) received three neoadjuvant cycles of DV (2.5 mg/kg) Q3W, sintilimab (200 mg) Q3W, and XELOX Q3W, followed by surgery at 3-4 weeks and three same adjuvant cycles. Primary endpoint: pathological complete response (pCR). Secondary: major pathological response (MPR), clinical downstaging rate (CDR), disease-free survival (DFS), overall survival (OS), safety. Exploratory: circulating tumor DNA (ctDNA) dynamics and PD-L1 expression. Results: As of August 20, 2025, 28 patients were enrolled in the study. HER2 status was 2+ in 16 patients (57.1%; including 8 FISH status not assessed, 3 positives, and 5 negatives) and 3+ in 12 patients (42.9%). PD-L1 CPS was <1 in 9 patients (32.1%), ≥1 in 14 (50.0%), and not assessed in 5 (17.9%). Baseline staging included cT3N+M0 in 18 patients (64.3%) and cT4N+M0 in 10 patients (35.7%). Among 18 patients undergoing surgery (excluding 2 declinations and 8 ongoing neoadjuvant), R0 resection was achieved in 100%, with pCR (pT0N0M0) in 38.9% (7/18) and MPR in 55.6% (10/18), and clinical regression was observed in 83.3% (15/18). Median DFS and OS were not reached. Serial ctDNA sampling remains ongoing. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 25.0% (7/28), predominantly hematologic toxicities: neutropenia (14.3%), thrombocytopenia (7.1%), anemia (3.6%), lymphopenia (3.6%), and leukopenia (3.6%), with no treatment-related deaths. Conclusions: Preliminary findings indicate that the perioperative administration of DV, Sintilimab, and XELOX demonstrates promising efficacy and a favorable safety profile in patients with locally advanced, resectable HER2-overexpressing G/GEJ adenocarcinoma. Clinical trial information: NCT06227325 .